The literature presents strong genetic evidence of a gene-disease association with multiple unrelated individuals with overlapping phenotypes (intellectual disability, overgrowth, variable dysmorphic features) found to have loss-of-function and/or missense variants in BRWD3. In several cases, the BRWD3 variant was shown to segregate with disease in extended families.
Emerging experimental evidence (primarily studies of drosophila) also supports a role for variants in BRWD3 as causative of syndromic ID.
Note: Actual segregation points awarded for this curation is 2 but the change does not alter the final classification as definitive.
Note: There are additional reported patients in the literature with loss-of-function and/or de novo variants in BRWD3. Inclusion of all reported patients was not necessary as the maximum points for genetic evidence had already been reached.
BRWD3 was first reported in relation to X-linked syndromic intellectual disability in 2007 (Field et al., PMID: 17668385). The literature reports multiple unrelated individuals with overlapping phenotypes (intellectual disability, overgrowth, and variable dysmorphic features) found to have loss-of-function or missense variants in BRWD3.
Ten variants (nonsense, frameshift, splice, missense) that have been reported in ten probands in three publications (PMIDs: 17668385, 24462886, 28475857) are included in this curation. In several cases, the variants were shown to segregate with disease in extended families. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. Emerging experimental evidence (primarily studies of drosophila) also supports this gene-disease relationship.
Note: The actual number of segregation points awarded for this curation is 2, but this change does not alter the final classification.
In summary, there is definitive evidence supporting the relationship between BRWD and X-linked syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 18, 2018 (SOP Version 5).
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